This invention relates to nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI). In particular, the invention relates to processes, devices and compounds for hyperpolarizing nuclei, and more specifically, to a method for carrying out an NMR experiment with enhanced sensitivity on a compound comprising hyperpolarizable nuclei.
NMR and MRI involve the detection of the transitions of nuclear spins between an excited state and a ground state in an applied magnetic field. Because the energy difference between these states is often small, the usual Boltzmann distribution of chemically identical nuclei is such that at room temperature the populations of nuclear spin states which are in dynamic equilibrium are almost identical. Since the strength of the detected signal in magnetic resonance experiments is proportional to the population difference, NMR signals are typically weak.
The strength of detectable NMR signals can however be enhanced by hyperpolarizing the magnetic nuclei. Hyperpolarization (also known as pre-polarization) in this context refers to a process in which a significant excess of magnetic nuclei are induced into the same spin state. This results in a large increase in available signal due to the much larger inequality of populations across the energy levels. In order for a hyperpolarized state to be useful, it is important that the spin state is sufficiently long lived to provide useful information, i.e. that the relaxation time of the spin state is ‘long’. The rules governing the relaxation rates of nuclear spins are complex but known. It suffices to say that certain nuclei and spins systems have relaxation times which may extend to hours, days, months or even years.
There are a number of ways to induce certain nuclei into a hyperpolarized state. The simplest way is to cool the material to very low temperatures in the presence of a magnetic field, which will favour population of the lower energy state in which the spins of the nuclei are aligned with the applied magnetic field. This method is suitable for the production of hyperpolarized monatomic gases such as xenon or helium-3. The polarization levels of these nuclei have also been increased via the use of laser-based technologies.
One molecule that can be readily polarized is dihydrogen. Dihydrogen exists in various spin states, in which the spins of the individual nuclei are either aligned (ortho, the higher energy state), or opposed (para, the lower energy spin state). Para-hydrogen (p-H2) is a nuclear spin isomer of dihydrogen with the spin configuration αβ-βα. Para-hydrogen has no net magnetic moment and is therefore unobservable in this form by magnetic resonance methods. The ortho forms however retain magnetic resonance activity. The binuclear spin system of dihydrogen can be hyperpolarized simply by cooling to low temperature in the presence of a suitable catalyst which promotes conversion to the lower energy para-hydrogen state. In this process, the role of the catalyst is to perturb the dihydrogen molecule and thereby reduce its symmetry; otherwise a quantum mechanical selection rule prevents interconversion between the two spin states. Once separated from the catalyst and returned to room temperature, the para-hydrogen spin state may last for over a year in the absence of external effects.
Nuclei can be hyperpolarized by a process known as para-hydrogen induced polarization (PHIP). PHIP has proved to be highly efficient and has currently achieved greater enhancement of heteronuclei NMR signals than other methods known in the art. PHIP is generally the result of a chemical reaction in which the para-hydrogen nuclei are transferred into another molecule having certain symmetry properties. Under the right circumstances, the spin state of the para-hydrogen molecule is preserved in the spins of the two hydrogen atoms which become part of the new molecule. If other NMR-active nuclei are within coupling distance of the hydrogen nuclei, spin polarization of those nuclei can be transferred spontaneously. In this way, the signals of heteronuclei such as 13C, 15N and 31P can be enhanced. By way of example, WO 99/24080 describes a PHIP process in which para-hydrogen is added across a symmetrical carbon-carbon double bond containing a 13C centre. In one example of such a process, Wilkinson's catalyst is first reduced by addition of para-hydrogen, followed by addition of an ethylene ligand. The resulting hydride ligands then undergo a migratory insertion reaction with the ethylene ligand, which subsequently dissociates from the complex to form uncoordinated hyperpolarized ethane. An overview of PHIP is given in Blazina et al, Dalton Trans., 2004, 2601-2609.
Conventional PHIP processes involve the chemical addition of para-hydrogen to hydrogenatable substrates (compounds), usually organic substrates (compounds) containing double and triple bonds. This processes are therefore limited to substrates (compounds) capable of undergoing dihydrogenation. Furthermore, hydrogen equivalence is not preserved at all stages, which leads to some loss of hyperpolarization through relaxation.
It is the object of the invention to present a method for carrying out an NMR experiment on a compound comprising hyperpolarizable nuclei, wherein polarization is transferred to the hyperpolarizable nuclei of the compound, which is easier to perform and which can be applied to a broader scope of compounds, in particular compounds that may not undergo a hydrogenation reaction.